2-amino-4,5,7,8-tetrahydro-6h-thiazolo or oxazolo(5,4-d)azepines and salts

ABSTRACT

COMPOUNDS OF THE FORMULA   2-(R2-NH-),6-R1-5,6,7,8-TETRAHYDRO-4H-THIAZOLO(4,5-D)-   AZEPINE OR   2-NH2,6-R1-5,6,7,8-TETRAHYDRO-4H-OXAZOLO(4,5-D)AZEPINE   WHEREIN R1 IS HYDROGEN, STRAIGHT OR BRANCHED ALKYL OF 1 TO 4 CARBON ATOMS, HYDROXY-ALKYL OF 1 TO 4 CARBON ATOMS, ALKYL, CHLOALKYL, HEXAHYDROBENZYL, PHENYL, PHENETHYL, BENZYL, MONO-OR DI-HAOBENZYL OR (ALKYL OR 1 TO 3 THOXYBENZYL, TRIFULOROMETHYL-BENZYL OR (ALKYL OF 1 TO 3 CARBON ATOMS)-BENZYL, AND R2 IS HYDROGEN, STRAIGHT OR BRANCHED ALKYL OF 1 TO 5 CARBON ATOMS, ALLYL, CYCLOALKYL, PHENYL, BENZYL OR PHENETHYL, AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, THE COMPOUNDS AS WEL AS THEIR SALTS ARE USEFUL AS HYPOTENSIVES, SEDATIVES, ANTITUSSIVES AND ANTIPHLOGISTICS.

United States Patent 3,804,849 2-AM]N0-4,5,7,8-TETRAHYDRO-6H-THIAZOL0 0R0XAZOL0[5,4-d]AZEPINES AND SALTS Gerhart Griss, Manfred Kleemann,Wolfgang Grell, and

Helmut Ballhause, Biberach am der Riss, Germany, assignors to BoehringerIngelheim GmbH, Ingelheim am Rhein, Germany No Drawing. Filed Aug. 4,1971, Ser. No. 169,065 Claims priority application, Germany, Aug. 14,1970, P 20 40 510.1; June 2, 1971, P 21 27 267.3 Int. Cl. C07d 99/04,99/10 U.S. Cl. 260306.8 F 10 Claims ABSTRACT OF THE DISCLOSURE Compoundsof the formula wherein R is hydrogen, straight or branched alkyl of l to4 carbon atoms, hydroxy-alkyl of 1 to 4 carbon atoms, allyl, cycloalkyl,hexahydrobenzyl, phenyl, phenethyl, benzyl, monoor di-halobenzyl, mono-,dior trimethoxybenzyl, trifluoromethyl-benzyl or (alkyl of l to 3 carbonatoms)-benzyl, and

R is hydrogen, straight or branched alkyl of 1 to 5 carbon atoms, allyl,cycloalkyl, phenyl, benzyl or phenethyl,

and non-toxic, pharmacologically acceptable acid addition salts thereof;the compounds as well as their salts are useful as hypotensives,sedatives, antitussives and antiphlogistics.

The present invention relates to novel 2-amino-4,S,7,8- tetrahydro 6Hthiazolo or oxazolo[5,4-d]azepines and non-toxic acid addition saltsthereof, as well as to methods of preparing these compounds.

More particularly, the present invention relates to a novel class offused-ring compounds of the formula m-N C--NHRa N Ri-N \C-NH:

0 (Ia) wherein R is hydrogen, straight or branched alkyl of 1 to 4carbon atoms, hydroxy-alkyl of 1 to 4 carbon atoms, allyl, cycloalkyl,hexahydrobenzyl, phenyl, phenethyl, benzyl, monoor di-halobenzyl, mono-,dior tri-methoxybenzyl, trifluoromethyl-benzyl or (alkyl of 1 to 3carbon atoms)-benzyl, and

R is hydrogen, straight or branched alkyl of 1 to 5 carbon atoms, allyl,cycloalkyl, phenyl, benzyl or phenethyl,

3,804,849 Patented Apr. 16, 1974 and non-toxic, pharmacologicallyacceptable acid addition salts thereof.

The compounds embraced by Formulas I and Ia may be prepared as follows:

METHOD A By reacting a hydrohalic acid addition salt of aS-haloazepin-4-one of the formula Hal wherein R; has the same meaningsas in Formulas I and Ia, and Hal is chlorine, bromine or iodine, withurea or a thiourea of the formula s H N-'l-NH-Rz wherein R has the samemeanings as in Formula I.

The reaction is preferably performed in the molten state and, ifnecessary, in the presence of a catalytic amount of an acid, such asglacial acetic acid; however, it may also be performed in the presenceof a solvent medium.

When the S-halo-azepinone salt (II) is reacted with a thiourea (III),the reaction may be performed, for example, in the presence of a solventmedium, such as an aliphatic alcohol, dimethylformamide, glacial aceticacid, water or a mixture of any two or more of these, at a temperaturebetween room temperature and the boiling point of the solvent medium,and optionally in the presence of an acid-binding agent.

When the S-halo-azepinone salt is reacted with urea, the reaction maylikewise be performed in the presence of a solvent medium, such asethanol, isopropanol, tert.-butanol, glacial acetic acid, dioxane,dimethylformamide or a mixture of any two or more of these, at atemperature up to the boiling point of the solvent medium, andoptionally in the presence of an acid, such as glacial acetic acid.

Examples of suitable acid-binding agents are inorganic bases, such assodium carbonate or potassium carbonate, or tertiary organic bases, suchas triethylamine or pyridine. When used in commensurate excess, theorganic base may simultaneously serve as the solvent medium.

METHOD B For the preparation of a compound of the Formula I wherein R ishydroxyalkyl of 1 to 4 carbon atoms, by reacting a 2 acylamino 4,5,7,8tetrahydro-GH-thiazolo [5,4-d1azepine of the formula wherein R has thesame meanings as in Formula I and Ac is carboxylic acyl, such asbenzoyl, 'with an alkyleneoxide of the formula wherein R is hydrogen oralkyl of 1 to 2 carbon atoms, followed by removal of the acyl radical byacid hydrolysis.

The reaction is preferably performed in the presence of a solvent, suchas methanol, and at temperatures between 0 and 25 C. If the reactionrequires higher temperatures, it is advantageously performed in apressure vessel, such as an autoclave.

The subsequent acid hydrolysis is performed in the presence of an inertsolvent at temperatures up to the boiling point of the solvent, pursuantto conventional methods.

The compounds embraced by Formulas I and Ia are organic bases andtherefore form acid addition salts with inorganic or organic acids.Examples of non-toxic, pharmacologically acceptable acid addition saltsare those formed with hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, tartaric acid, succinic acid, citric acid, adipicacid, pamoic acid, fumaric acid, maleic acid, 8-chlorotheophylline orthe like.

The starting compounds of the Formula II for method A may be prepared byhalogenating the corresponding azepin-4-ones in glacial acetic acid withan equimolar amount of chlorine, bromine or iodine, and do not need tobe purified prior to use as starting compounds in this method.

Some of the azepin-4-ones needed for the preparation of startingCompounds II are described in the literature [see Ak. Yokov et al.,Bull. Chem. Soc. Japan, 29, 631 1959)]. The l-substituted azepin-4-ones,which are not described in the literature, may be prepared by theDieckmann condensation (Organic Reactions, 15, 1-203) of ethylN-substituted N-(2'-ethoxycarbonyl-ethyl)-4-aminobutyrates, usingpreferably potassium tert.-butylate or sodium hydride as thecondensation agent, followed by hydrolysis and decarboxylation of themixture of l-substituted ethyl hexahydro-4H-azepin-4-one-3- andS-carboxylates intermediates in the presence of acids. The IR band ofthe carbonyl group of these compounds lies at 1695-1700 cmr (methylenechloride), and that of their salts at 1720 cm.- (KBr).

The starting compounds of the Formula IV for method B may be obtained byreacting 5-bromo-azepin-4-one with correspondingly N-acylated thiourea.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood, however, that the invention is not limited solelyto the particular examples given below.

EXAMPLE 1 Z-amino-6-benzyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4- d]azepineand its dihydrochloride by method A A mixture consisting of 11 gm. (34.6millimols) of 1 benzyl-S-bromo-hexahydro-1H azepin-4-one hydrochloride[M.P. 158 C.; prepared from l-benzyl-hexahydro- 1H-azepin-4-onehydrochloride (M.P. 189 C.) by bromination with an equimolar amount ofbromine in glacial acetic acid], 50 ml. of water and 2.63 gm. (34.6millimols) of thiourea was stirred for 12 hours at room temperature.Thereafter, the reaction solution was adjusted to pH 12 with sodiumhydroxide, admixed with'20 ml. of methanol, and the mixture wasextracted with chloroform. The chloroform extracts were dried oversodium sulfate and evaporated. The residue, 2 amino-6-benzyl-4,5,7,8-tetrahydro-6H thiazolo[5,4-d]azepine, was dissolved in hot ethanol, andthe resulting solution was acidified with isopropanolic hydrochloricacid. Upon cooling, 6.2 gm. (51% of theory) of the dihydrochloride, M.P.233 C. (decomp.), of the formula 332.30) (percent): C, 50.70; H, 5.77;N, 12.65. Found (percent): C, 50.30; H, 5.84; N, 12.80.

4 EXAMPLE 2 A mixture consisting of 77.5 gm. (208 millimols) of 1-benzyl-S-bromo-hexahydro-4H-azepin 4 one hydrobromide, 600 ml. ofethanol and 15.8 gm. (208 millimols) of thiourea was heated at itsboiling point for two hours, during which time 2amino-6-benzyl-4,5,7,8-tetrahydro- 6H-thiazolo[5,4-d]azepinehydrobromide crystallized out. After cooling, the crystals werecollected by vacuum filtration, dissolved in water, the aqueous solutionwas adjusted to pH 12 with sodium hydroxide, and the free base liberatedthereby was extracted with chloroform. The chloroform extracts wereevaporated, the residue was dissolved in 100 ml. of hot ethanol, and thehot solution was admixed with 50 ml. of saturated isopropanolichydrochloric acid and 100 ml. of ethyl acetate. Upon cooling, 40 gm.(59% of theory) of 2 amino-6-benzyl-4,5,7,8- tetrahydro-6Hthia2olo[5,4-d]azepine dihydrochloride, M.P. 233 C. (decomp.),crystallized out.

EXAMPLE 3 11 gm. (34.6 millimols) of 1benzyl-5-bromo-hexahydro-4H-azepin-4-one hydrobromide and 3.63 gm. (34.6millimols) of thiourea were intimately admixed with each other, and themixture was melted by heating it to between and C. for 10 minutes.Thereafter, the molten mass was allowed to cool, was then dissolved inwater, and the aqueous solution was made alkaline with sodium hydroxideand then thoroughly extracted with chloroform. The combined chloroformextracts were evaporated to dryness, the residual free base wasdissolved in hot ethanol, and the hot solution was acidified withisopropanolic hydrochloric acid. Upon addition of ethyl acetate, 3.1 gm.(25.5% of theory) of 2-arnino-6-benzyl- 4,5,7,8-tetrahydro 6Hthiazolo[5,4-d]azepine dihydrochloride, M.P. 233 C. (decomp.),crystallized out.

EXAMPLE 4 2-amino-6-benzyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d] azepinedihydrochloride by method A A solution of 6.1 gm. (30 millimols) ofl-benzyl-hexahydro-4H-azepin-4-one (B.P. 98-100 C. at 0.1 mm. Hg) in amixture of 100 ml. of glacial acetic acid and 15 m1. of a 40%hydrobromic acid solution in glacial acetic acid was admixed at roomtemperature with a solution of 4.8 gm. (30 millimols) in 50 ml. ofglacial acetic acid. The glacial acetic acid and the hydrobromic acidwere then distilled off in vacuo, the residual oily1-benZyl-5-bromohexahydro-4H-azepin-4-one hydrobromide was dissolved in200 ml. of ethanol, the ethanolic solution was admixed with 2.28 gm. (30millimols) of thiourea, and the mixture was heated at its boiling pointfor 2 hours. Upon cooling,

-arnino 6 benzyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d] azepinehydrobromide crystallized out, which was converted into itsdihydrochloride, M.P. 232 C., as described in Example 2. The yield was 6gm. (60% of theory).

Analysis.Calculated for C14H17N3S'2HC1 (mol. wt. 332.30) (percent): C,50.70; H, 5.77; N, 12.65. Found (percent): C, 50.49; H, 6.01; N, 12.58.

6I-I-thiazolo[5,4-d]azepine dihydrochloride, M.P. 236 C (decomp.), ofthe formula was prepared from 1-(p-fiuoro-benzyl)-hexahydro4H-azep1n-4-one hydrochloride (M.P. 208 C.). The yield was 55% oftheory.

Analysis.--Calculated for c,,H,,FN,s-2Hc1 (mol. wt. 350.29) (percent):C, 48.00; H, 5.17; N, 12.00. Found (percent): C, 48.00; H, 5.10; N,12.20.

EMMPLE 6 was prepared from 1-(p-chloro-benzyl)-hexahydro-4H-azepin-4-one hydrochloride (210 C.). The yield was 53% of theory.

Analysis.-Calculated for C H ClN S-2HCl (mol. wt. 366.74) (percent): C,45.86; H, 4.95; N, 11.46. Found (percent): C, 45.80; H, 5.03; N, 11.26.

EXAMPLE 7 Using a procedure analogous to that described in Example 4,2-amino-6-(m-chloro-benzyl)-4,5,7,8-tetrahydro- 6H-thiazolo[5,4-d]azepine dihydrochloride, M.P. 244 C., was prepared from1-(m-chlorobenzyl)-hexahydro-4H- azepin-4-one hydrochloride (212 C.).The yield was 46% of theory.

Analysis.Calculated for C H ClN S -2HCl (mol. wt. 366.74) (percent): C,45.86; H, 4.95; N, 11.46. Found (percent): C, 45.80; H, 5.09; N, 11.30.

EXAMPLE 8 Using a procedure analogous to that described in Example 4,2-amino-6-(m,p-dichloro-benzyl)-4,5,7,8-tetrahydro 6Hthiazolo[5,4-d]azepine dihydrochloride, M.P. 246 C. (decomp.), of theformula was prepared from 1-(m,p-dichloro-benzyl)-hexahydro-4H-azepin-4-one hydrochloride (IR spectrum in KBr: carbonyl band at 1720cm.- The yield was 28% of theory.

Analysis.-Calculated for C H Cl N S -2HC1 (mol. wt. 401.19) (percent):C, 41.91; H, 4.27; N, 10.47. Found (percent): C, 42.00; H, 4.20; N,10.32.

EXAMPLE 9 EXAMPLE 10 Using a procedure analogous to that described inExample 4, 2 amino-6-(o,p-dichloro-benzy1)-4,5,7,8-tetrahydro 6Hthiazolo[5,4-d] azepine dihydrochloride, M.P. 230 C. (decomp.), wasprepared from 1 (o,p-dichlorobenzyl)-hexahydro 4H azepin 4 onehydrochloride (IR Spectrum in KBr: canbonyl band at 1720 cm.- The yieldwas 56% of theory.

Analysis.Calculated for C H C1 N S-2HCl (mol.

wt. 401.19) (percent): C, 41.91; H, 4.27; N, 10.47. Found (percent): C,41.90; H, 4.43; N, 10.75.

6 EXAMPLE 11 Using a procedure analogous to that described in Example 4,2 amino 6 (p-bromo-benzyl)-4,5,7,8-tetrahydro 6H thiazolo[5,4-d]azepinedihydrochloride, M.P. 251 C. (decomp.), was prepared froml-(p-bromobenzyl)-hexahydro-4H-azepin-4-one hydrochloride (M.P. 215 C.).The yield was 49% of theory.

Analysis-Calculated for C H BrN S-2HCl (mol. wt. 411.20) (percent): C,40.89; H, 4.41; N, 10.22. Found (percent): C, 40.85; H, 4.56; N, 9.95.

EXAMPLE 12 Using a procedure analogous to that described in Example 4, 2amino 6 (o-bromo-benzyl)-4,5,7,8-tetrahydro 6H thiazolo[5,4-d]azepinedihydrochloride, M.P. 233 C. (decomp.), was prepared from1-(o-bromobenzy1)-hexahydro 4H azepin 4 one hydrochloride (M.P. 179 C.).The yield was 18% of theory.

Analysis.-Calculated for C H BrN S-2HCl (mol. wt. 411.20) (percent): C,40.89; H, 4.41; N, 10.22. Found (percent): C, 41.20; H, 4.66; N, 9.85.

EXAMPLE 13 Using a procedure analogous to that described in Example 4, 2amino 6 (m-bromo-benzyl)-4,5,7,8-tetrahydro 6H thiazolo[5,4-d] azelpinedihydrochloride, M.P. 255 C. (decomp.), of the formula was prepared froml-(m-bromo benzyl)-hexahydro-4H- azepin-4-one hydrochloride (M.P. 192C.). The yield was 20% of theory.

Analysis.--Calculated for C H BrN S-2HCl (mol. wt. 411.20) (percent): C,40.89; H, 4.41; N, 10.22. Found (percent): C, 40.85; H, 4.57; N, 10.08.

EXAMPLE 14 Using a procedure analogous to that described in Example 2, 2amino 6 (p-methyl-benzyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepinedihydrochloride, M.P. 239 C. (decomp.), of the formula CE nHPQ NHM wasprepared from l-(p-methyl-benzyl)-5-bromo-hexahydro-4H-azepin-4-onehydrobromide (M.P. 156 C.). The yield was 20% of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 346.32) (percent): C,52.02; H, 6.11; N, 12.13. Found (percent): C, 51.90; H, 6.29; N, 12.28.

EXAMPLE 15 EXAMPLE 16 Using a procedure analogous to that described inExample 4, 2 amino 6 (m-methyl-benzyl)-4,5,7,8-tetrahydro 6Hthiazolo[5,4-d]azepine dihydrochloride, M.P. 233 C. (decomp.), wasprepared from l-(m-methylbenzyl)-hexahydro-4H-azepin-4-one hydrochloride(M.P. 169 0.). The yield was 30% of theory.

7 Analysis-Calculated for C H N S-2HCl (mol. wt. 346.32) (percent): C,52.02; H, 6.11; N, 12.13. Found (percent): C, 52.30; H, 6.30; N, 12.35.

EXAMPLE 17 Using a procedure analogous to that described in Example 4, 2amino 6 (p trifluoromethyl-benzyl)-4,5, 7,8 tetrahydro 6Hthiazolo[5,4-d1azepine dihydrochloride, M.P. 237-238 C., of the formulawas prepared from 1-(p-trifluoromethyl-benzyl)-hexahydro-4H-azepin-4-onehydrochloride (IR spectrum: car- 'bonyl hand at 1700 cm.- The yield was30% of theory.

Analysis.- Calculated for C H F N S-2HCl (mol. wt. 400.30) (percent): C,45.01; H, 4.54; N, 10.50. Found (percent): C, 44.80; H, 4.74; N, 10.41.

EXAMPLE 18 Using a procedure analogous to that described in Example 4,2-amino-6-(m-trifiuoromethyl-benzyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d1azepinedihydrochloride, M.P. 246 C. (decomp.), was prepared froml-(m-trifluoromethylbenzyl)-hexahydro-4H-azepin-4-one hydrochloride(M.P. 176-178 C.). The yield was 25.5% of theory.

Analysis-Calculated for C H F N S-2 HCl (mol. Wt 400.30) (percent): C,45.01; 'H, 4.54; N, 10.50. Found (percent): C, 44.80; H, 4.74; N, 10.41.

EXAMPLE 19 Using a procedure analogous to that described in Example 4,2-amino-6-(p-methoxy-benzyl)-4,5,7,8-tetrahydro- 6H-thiazolo[5,4-d]azepine dihydrochloride, M.P. 230 C. (decomp.), of the formula wasprepared from l-(p-methoxy-benzyl)-hexahydro-4H- azepin-4-0nehydrochloride (IR spectrum in KBr: carbonyl band at 1720 cmr The yieldwas 31% of theory.

Analysis.Calculated for C H ON S-2 HCl (mol. wt. 362.32) (percent): C,49.72; H, 5.84; N, 11.59. Found (percent): C, 49.70; H, 5.96; N, 11.85.

EXAMPLE 20 Using a procedure analogous to that described in Example 4,2-amino-6-(m,p-dimethoxy-benzyl)-4,5,7,8-tetrahydro 6H thiazolo[5,4d]azepine dihydrochloride, M.P. 238 C. (decomp.), of the formula 0011. NomoQcm-Nj I -nmznor was prepared from1-(m,p-dimethoxy-benzyl)-hexahydro- 4H-azepin-4-one hydrochloride (IRspectrum in K-Br: carbonyl band at 1720 cmr' The yield was 44% oftheory.

Analysis.Calculated for C I-I O N S- 2HCl (mol. wt. 392.35) (percent):C, 48.99; H, 5.91; N, 10.72. Found (percent): C, 49.00; H, 5.65; N,10.53.

EXAMPLE 21 Using a procedure analogous to that described in Example 4,2-amino-6-(3',5'-dimethoxy-benzy1)-4,5,7,8-tetrahydro 6H thiazolo[5,4d]azepine dihydrochloride, M.P. 215 C. (decomp.), was prepared from1-(3,5'-dimethoxy-benzyl)-hexahydro-4H-azepin-4-one hydrochloride 8 (IRspectrum in KBr: carbonyl band at 1720 cmr The yield was 28% of theory.

Analysis-Calculated for C H O N S-2 HCl (mol. wt. 392.35) (percent): C,48.99; H, 5.91; N, 10.72. Found (percent): C, 48.80; H, 6.20; N, 10.40.

EXAMPLE 22 EXAMPLE 23 Using a procedure analogous to that described inExample 4,2-arnino-6-(3',5',5-trimethoxy-benzyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine dihydrochloride, M.P. 230 C. (decomp.), of theformula was prepared from1-(3',4,5'-trimethoxy-benzyl-hexahydro-4H-azepin-4-one hydrochloride (IRspectrum in KBr: carbonyl band at 1720 cmr The yield was 53% of theory.

Analysis.-Calculated for C H O N S'2 HCl (mol. wt. 422.38) (percent): C,48.34; H, 5.97; N, 9.95. Found (percent): C, 48.20; H, 5.96; N, 10.00.

EXAMPLE 24 Using a procedure analogous to that described in Example 4,2-amino-6-phenyl-4,5,7,8 tetrahydro 6H-thiazolo[5,4-d]azepinedihydrochloride, M.P. 202 C. (decomp.), of the formula was prepared from1-phenyl-hexahydro-4H-azepin-4-one hydrochloride (M.P. 144 C.). Theyield was 14% of theory.

Analysis.Calculated for C H N S'2HCl (mol. wt. 318.27) (percent): C,49.05; H, 5.39; N, 13.20. Found (percent): C, 49.30; H, 5.50; N, 13.45.

EXAMPLE 25 Using a procedure analogous to that described in Example 4,2-amino-6-(fl-phenethyl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4 d]azepinedihydrochloride, M.P. 226 C. (decomp.), of the formula was prepared from1-( ,B-phenethyl)-hexahydro-4H-azepin- 4-one (B.P. -134 C. at 0.4 mm.Hg). The yield was 17.5% of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 346.32) (percent): C,52.02; H, 6.12; N, 12.11. Found (percent): C, 52.20; H, 6.21; N, 12.17.

EXAMPLE 26 Using a procedure analogous to that described in Example 4,2-amino-6-(a-phenethyl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4 d]azepinedihydrochloride, M.P. 204 C.

9 (decomp.), was prepared from l-(u-phenethyn-hexahydro-4H-azepin-4-one(B.P. 105 C. at 0.1 mm. Hg). The yield was 32% of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 346.32) (percent): C,52.02; H, 6.12; N, 12.11. Found (percent): C, 52.50; H, 6.29; N, 11.60.

EXAMPLE 27 Using a procedure analagous to that described in Example 4,2-amino-4,5,7,8-tetrahydro 6H-thiazolo [5,4-d] azepine dihydrochloride,M.P. 254 C. (decomp.), of the was prepared from hexahydro-4H-azepin 4one hydrochloride (M.P. 177-178 C.). The yield was 18% of theory.

Analysis.Calculated for C I-I N S-2HCl (mol. wt. 242.17) (percent): C,34.72; H, 5.41; N, 17.35. Found (percent): C, 35.00; H, 5.45; N, 17.50.

EXAMPLE 28 Using a procedure analogous to that described in Example 1,2-amino-6-methyl-4,5,7,8 tetrahydro 6H-thiazolo[5,4d]azepinedihydrochloride, M.P. 257 C. (decomp.), of the formula was prepared froml-methyl bromo-hexahydro 4H- azepin-4-one hydrobromide (M.P. 110 C.).The yield wa 52% of theory.

Analysis.Calculated for C,,H N S-2HCl (mol. wt. 256.20) (percent): C,37.50; H, 5.90; N, 16.40. Found (percent): C, 37.45; H, 6.27; N, 16.35.

EXAMPLE 29 Using a procedure analogous to that described in Examples 1and 2, 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d] azepinedihydrochloride, M.P. 228 C. decomp.), was prepared from1-ethyl-S-bromo-hexahydro- 4H-azepin-4-one hydrobromide (M.P. 138 C.).The yield was 52% of theory.

Analysis.-Calculated for C H N S-2HCl (mol. wt. 270.23) (percent): C,40.01; H, 6.34; N, 15.55. Found (percent): C, 39.90; H, 6.28; N, 15.32.

EXAMPLE 30 Using. a procedure analogous to that described in Example 1,2-amino-6-n-propyl 4,5,7,8-tetrahydro-6H- thiazolo[5,4-d] azepine, M.P.145 C., was prepared from 1-n-propyl-S-bromo-hexahydro 4H-azepin-4-0nehydrobromide (M.P. 126 C.). The yield was 56% of theory.

Analysis.Calculated for C H N S (mol. wt. 211.32) (percent): C, 56.27;H, 8.11; N, 19.88. Found (percent): C, 56.65; H, 8.05; N, 19.75.

EXAMPLE 31 Using a procedure analogous to that described in Examples 1and 2, 2-amino-6-isopropyl-4,5,7,8-tetrahydro-6H thiazolo[5,4-d]azepinedihydrochloride, M.P.

225 C. (decomp.), was prepared from l-isopropyl-S-bromo-hexahydro-4I-I-azepin-4-one hydrobromide (M.P.

114 C.). The yield was 35% of theory.

Analysis.-Calculated for C10H17N3S'2HC]. (mol. wt. 284.25) (percent): C,42.25; H, 6.74; N, 14.78. Found (percent): C, 41.90; H, 7.05; N, 14.40.

EXAMPLE 32 Using a procedure analogous to that described in Examples 1and 2, 2-amino-6-n-butyl-4,5,7,8-tetrahydro- 6H-thiazolo[5,4-d]azepinedihydrochloride, M. P. 254- 256 C. (decomp.), was prepared froml-n-butyl-S-bromo-hexahydro 4H-azepin-4-one hydrobromide (M.P. 144 C.).The yield was 59% of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 298.28) (percent): C,44.29; H, 7.10; N, 14.08. Found (percent): C, 44.20; H, 6.88; N, 13.86.

EXAMPLE 33 Using a procedure analogous to that described in Example 1,Z-amino 6 isobutyl-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepinedihydrochloride, M.P. 238 C. (decomp.), was prepared from1-isobuty1-5-bromo-hexahydro-4H-azepin-4-one hydrobromide. The yield was41% of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 298.28) (percent): C,44.29; H, 7.10; N, 14.08. Found (percent): C, 44.50; H, 7.10; N, 13.96.

EMMPLE 34 EXAMPLE 35 Using a procedure analogous to that described inExample 1, 2-amino-6-(tert.buty1) 4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine dihydrochloride, M.P. 224 C. (decomp.), wasprepared from 1-(tert.butyl)-5-bro mo-hexahydro 4H-azepin-4one-hydrobromide (M.P. 182 C.). The yield was 29% of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 298.28) (percent): C,44.29; H, 7.10; N, 14.08. Found (percent): C, 44.10; H, 7.26;'N, 13.88.

EXAMPLE 36 Using a procedure analogous to that described in Example 4,2-amino 6 allyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepinedihydrochloride, M.P. 245 C. (decomp.), of the formula was prepared from1-ally1-hexahydro-4H-azepin-4one (B.P. 52-54 C. at 0.2 mm. Hg). Theyield was 67% of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 282.24) (percent): C,42.51; H, 6.07; N, 14.88. Found (percent): C, 42.60; H, 6.03; N, 14.90.

EXAMPLE 37 Using a procedure analogous to that described in Example 4,2-amino-6-hexahydrobenzyl 4,5,7,8-tetrahydro-6H thiazolo[5,4-d]azepinedihydrochloride, M.P. 240 C. (decomp.), of the formula was prepared from1-hexahydrobenzyl-hexahydro-4H- azepin-4-one hydrochloride (M.P. 180C.). The yield was 40% of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 338.45) (percent): C,49.69; H, 7.45; N, 12.42. Found (percent): C, 49.40; H, 7.36; N, 12.40.

1 1 EXAMPLE 38 Using a procedure analogous to that described in Example1, Z-methylamino 6 ethyl-4,5,7,8-tetrahydro- 6H-thiazolo[5,4-d]azepinedihydrochloride, M.P. 206 C. (decomp.), of the formula N CaHs-N INHCHa-2HC1 S was prepared from 1-ethyl-5-bromo-hexahydro-4H-azepin-4-one hydrobromide (M.P. 138 C.) and N-methyl-thiourea. The yield was27% of theory.

Arzalysis.Calculated for C H N S-2HCl (mol. wt. 284.31) (percent): C,42.30; H, 6.75; -N, 14.80. Found (percent): C, 41.90; H, 7.05; N, 14.48.

EXAMPLE 39 Using a procedure analogous to that described in Example l,2-ethylamino 6 ethyl-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepinedihydrochloride, M.P. 231 C. (decomp.), was prepared froml-ethyl-S-bromo-hexahydro-4H-azepin-4-one hydrobromide (M.P. 138 C.) andN-ethyl-thiourea. The yield was 30% of theory.

Analysis.-Ca1culated for C H N S-2HCl (mol. wt. 298.34) (percent): C,44.30; H, 7.09; N, 14.10. Found (percent): C, 44.65; H, 6.97; N, 13.93.

EXAMPLE 40 EXAMPLE 41 Using a procedure analogous to that described inExample l, 2-isopropylamino 6 ethyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine dihydrochloride, M.P. 244 C. (decomp.), wasprepared from l-ethyl-S-bromo-hexahydro-4H-azepin 4 one hydrobromide(M.P. 138 C.) and N-isopropyl-thiourea. The yield was 55 of theory.

Analysis.Calculated for C H N S-2HCl (mol. wt. 312.36) (percent): C,46.20; H, 7.42; N, 13.45. Found percent): C, 46.15; H, 7.41; N, 13.60.

EXAMPLE 42 Using a procedure analogous to that described in Example 4,2-ethylamino 6 a1lyl-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine, M.P.60 C., of the formula was prepared from l-allylhexahydro-4H-azepin-4-one (B.P. 52-54 C. at 0.2 mm. Hg) andN-ethyl-thiourea. The yield was 26% of theory.

Analysis.-Calculated for C H N S (mol. wt. 237.35) (percent): C, 60.75;H, 8.05; N, 17.73. Found (percent): C, 60.50; H, 8.16; N, 17.60.

EXAMPLE 43 Using a procedure analogous to that described in Example 4,2-n-amylamino 6 allyl-4,5,7,8-tetrahydro- 6H-thiazol0[5,4-d]azepine,M.P. 20 C., was prepared from l-allyl-hexahydro 4H azepin-4-one (B.P.52-54 C. at 0.2 mm. Hg) and N-n-amyl-thiourea. The yield was 54% oftheory.

12 Analysis.Calculated for C H N S (mol. Wt. 279.43) (percent): C,64.50; H, 9.03; N, 15.04. Found (percent): C, 64.75; H, 9.01; N, 14.75.

EXAMPLE 44 Using a procedure analogous to that described in Example 4,2-allylamino 6 allyl-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d1azepinedihydrochloride, M.P. 20 C., of the formula was prepared from1-allyl-hexahydro-4H-azepin-4-0ne (B.P. 5254 C. at 0.2 mm.Hg) andN-allyl-thiourea, The yield was 48% of theory.

Analysis-Calculated for C H N S (mol. wt. 249.36) (percent): C, 62.62;H, 7.68; N, 16.85. Found (percent): C, 62.60; H, 7.64; N, 16.60.

EXAMPLE 45 Using a procedure analogous to that described in Example 4,2-cyclohexylamino 6 allyl-4,5,7,8-tetrahydro- 6H-thiazolo[5,4-d]azepine, M.P. 20 C., of the formula 'was prepared from1-allyl-hexahydro-4H-azepin-4-one (B.P. 52 54 C. at 0.2 mm. Hg) andN-cyclohexyl-thiourea. The yield was 30% of theory.

Analysis.-Calculated for C H N S (mol. wt. 291.44) (percent): C, 65.99;H, 8.65; N, 14.44. Found (percent): C, 66.20; H, 8.67; N, 14.37.

EXAMPLE 46 Using a procedure analogous to that described in Example 4,2-phenylamino 6 allyl-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepinedihydrochloride, M.P. C., of the formula was prepared from 1allyl-hexahydro-4H-azepin-4-one (B.P. 52-54" C. at 0.2 mm. Hg) andN-phenyl-thiourea. The yield was 52% of theory.

Analysis-Calculated for C H N S-2HCl mol. wt. 358.39) (percent): C,53.60; H, 5.91; N, 11.73. Found (percent): C, 53.40; H, 6.13; N, 11.47.

EXAMPLE 47 Using a procedure analogous to that described in Example 4,2-methylamino-6-benzyl-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine,M.P. 117 C., of the formula was prepared from1-benzy1-hexahydro-4H-azepin-4-one (B.P. 98-100 C. at 0.1 mm. Hg) andN-methyl-thiourea. The yield was 22% of theory.

Analysis.-Calculated for C H N S (mol. wt. 237.39) (percent): C, 65.95;H, 7.05; N, 15.35. Found (percent): C, 65.70; H, 6.99; N, 15.20.

13 EXAMPLE 48 Using a procedure analogous to that described in Example4, except that isopropanol was used as the solvent instead of ethanol,2-ethy1amino 6 benzyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, M.P.86 C., was prepared from l-benzyl-hexahydro 4H azepin-4-one (B.P. 98-100C. at 0.1 mm. Hg) and N-methyl-thiourea. The yield was 44% of theory.

Analysis.Calculated for C H N S (mol. wt. 287.42) (percent): C, 66.90;H, 7.36; N, 14.61. Found (percent): C, 66.70; H, 7.15; N, 14.35.

EXAMPLE 49 Using a procedure analogous to that described in Example 48,2-n-propylarnino 6 benzyl-4,5,7,8-tetrahydro- 6H-thiazolo[5,4d] azepine,M.P. 80 C., was prepared from 1-benzy1-hexahydro-4H-azepin-4-one (B.P.98-100 C. at 0.1 mm. Hg) and N-n-propyl-thiourea. The yield was 50% oftheory.

Analysis-Calculated for C H N S (mol. wt. 301.44) (percent): C, 67.74;H, 7.69; N, 13.92. Found (percent): C, 67.90; H, 7.67; N, 13.90.

EXAMPLE 50 Using a procedure analogous to that described in Example 48,2-isopropylamino 6 benzyl-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine,M.P. 96 C., was prepared from 1-benzyl-hexahydro-4H-azepin-4-one (B.P.98100 C. at 0.1 mm. Hg) and N-isopropyl-thiourea. The yield was 60% oftheory.

Analysis.-Calculated for C17H23N3S (mol. Wt. 301.44) (percent): C,67.74; H, 7.69; N, 13.92. Found (percent): C, 67.70; H, 7.64; N, 13.78.

EXAMPLE 51 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo[5,4-d] azepineand its dihydrochloride by method A 17 gm. (56.6 millimols) of1-ethyl-5-bromo-hexahydro- 4H-azepin-4-one hydrobromide were intimatelyadmixed with 10.5 gm. (175 millimols) of urea, and 1 ml. of glacialacetic acid was added to the mixture. The resulting mixture was meltedby heating to between 70 and 90 C. and was held at that temperature forfrom 5- to 8 hours. Thereafter, the molten mass was allowed to cool, wasthen dissolved in water, and the aqueous solution was adjusted to pH 12with sodium hydroxide and extracted with chloroform. The combinedchloroform extracts were dried and evaporated, and the residue wasrecrystallized :from ethyl acetate, yielding 4.2 gm. (41% of theory) ofthe free base, M.P. 152-153 C., of the formula The free base wasdissolved in ethanol, the resulting solution was acidified withisopropanolic hydrochloric acid, ether was added to the acidic solution,and the precipitate formed thereby was collected, yielding thedihydrochloride, M.P. 217-219 C. (decomp.).

Analysis.-Calculated for C H N O-2HCl (mol. wt. 254.06) (percent): C,42.56; H, 6.74; N, 16.54. Found (percent): C, 42.70; H, 6.84; N, 16.72.

EXAMPLE 2 Using a procedure analogous to that described in Ex- 14zolo[5,4-d]azepine, M.P. 122 C. (ether), and its dihydrochloride, M.P.221 C. (decomp.), of the formula were prepared from1-n-propy1-5-bromo-hexahydro-4H- azepin-4-one hydrobromide and urea. Theyield was 42% of theory.

Analysis.Calculated for C H N O-2HCl (mol. wt. 268.19) (percent): C,44.78; -H, 7.14; N, 15.67. Found (percent): C, 44.90; H, 7.26; N, 15.62.

EXAMPLE 53 Using a procedure analogous to that described in Example 51,2-amino-6-isopropyl-4,5,7,8-tetrahydro6H-oxazolo[5,4-d]azepine, M.P. C.,was prepared from 1- isopropyl-S-bromo-hexahydro-4H-azepin-4-onehydrobromide and urea. The yield was 38% of theory.

Analysis.-Calculated for C H N O (mol. wt. 195.25) (percent): C, 61.55;H, 8.77; N, 21.55 Found (percent): C, 61.75; H, 8.93; N, 21.80.

EXAMPLE 54 Using a procedure analogous to that described in Example 51,2-amino-6-n-butyl 4,5,7,8 tetrahydro-6H-oxazolo[5,4-d]azepinedihydrochloride, M.P. 210 C. (decomp.), was prepared from1-n-butyl-5-bromo-hexahydro- 4H-azepin-4-one hydrobromide and urea. Theyield was 41% of theory.

Analysis.Calculated for C H N O-2HCl (mol. wt. 282.28) (percent): C,46.72; H, 7.49; N, 14.86. Found (percent): C, 46.75; H, 7.53; N, 14.87.

EXAMPLE 55 Using a procedure analogous to that described in Example 51,Z-amino-6-isobutyl-4,5,7,8-tetrahydro-6H-oxazolo[5,4-d]azepinedihydrochloride, M.P. 210 C. (decomp.), was prepared froml-isobutyl-S-bromo-hexahydro-4Hazepin-4-one hydrobromide and urea. Theyield was 43% of theory.

Analysis-Calculated for C H N O-2HC1 (mol. wt. 282.28) (percent): C,46.72; H, 7.49; N, 14.86. Found (percent): C, 46.50; H, 7.52; N, 15.06.

EXAMPLE 5 6 Using a procedure analogous to that described in Example 51,2-amino-6-allyl-4,5,7,8-tetrahydro-6H-oxazolo- [5,4-d]azepinedihydrochloride, M.P. 209 C. (decomp.), of the formula was prepared froml-a1lyl-5-bromo-hexahydro-4H-azepin- 4-one hydrobromide and urea. Theyield was 12% of theory.

' Analysis.Calcu1ated for C H N O-2HCl (mol. wt. 266.24) (percent): C,45.10; H, 6.43; N, 15.80. Found (percent): C, 45.00; H, 6.52; N, 15.70.

EXAMPLE 5 7 Using a procedure analogous to that described in Example 51,2-amino-6-benzyl 4,5,7,8 tetrahydro-fiH-oxazolo[5,4-d]azepinedihydrochloride, M.P. 209 C. (decomp.), of the formula was prepared froml-benzyl-S-bromo-hexahydro-4H-azepin-4-one hydrobromide and urea. Theyield was 48% of theory.

Analysis.Ca1culated for C H N O-2HCl (mol wt. 316.24) (percent): C,53.20; H, 6.06; N, 13.29. Found (percent): C, 53.25; H, 6.25; N, 13.15.

EXAMPLE 8 Using a procedure analogous to that described in Example 51,2-amino-6-hexahydrobenzyl-4,5,7,8-tetrahydr0- 6H-oxazolo[5,4 d]azepinedihydrochloride, M.P. 228- 229 C. (decomp.), of the formula was preparedfrom l-hexahydrobenzyl 5 bromo hexahydro-5H-azepin-4-one hydrobromideand urea. The yield was 18% of theory.

Analysis-Calculated for C H N O-2HCl (mol. wt. 322.27) (percent): C,52.18; H, 7.85; N, 13.04. Found (percent): C, 51.90; H, 7.65; N, 12.90.

EXAMPLE 59 Using a procedure analogous to that described in Example 51,2 amino-6-(p-methyl-benzyl)-4,5,7,8-tetrahydro-6H oxazolo[5,4 d]azepinedihydrochloride, M.P. 204 C. (decomp.), of the formula N era-4111,: INHz-2HO1 was prepared from l-(p-methyl-benzyl) 5 bromo-hexahydro 4Hazepin-4-one hydrobromide and urea. The yield was 23 of theory.

Analysis.Calcu1ated for C15H19N3O'2HC1 (mol. "Wt. 330.24) (percent): C,54.56; H, 6.41; N, 12.72. Found (percent): C, 54.90; H, 6.98; N, 12.40.

EXAMPLE 602-amino-6-(p-hydroxy-ethyl)-4,5,7,8-tetrahydro-6H-thiazo1o[5,4d]azepinedihydrochloride by method B 20.5 gm. (137 millimols) ofhexahydro-4H-azepin-4- one were dissolved in a mixture consisting of 180ml. of glacial acetic acid and 20 ml. of a 40% hydrogen bromide solutionin glacial acetic acid, and brominated at room temperature with asolution of 22 gm. of bromine in 80 ml. of glacial acetic acid.Thereafter, the glacial acetic acid and the hydrogen bromide weredistilled off, the residual raw 5-bromo-hexahydro-4H-azepin-4-onehydrobromide was dissolved in 250 ml. of ethanol, 24.7 gm. ofN-benzoyl-thiourea were added, and the mixture was heated at its boilingpoint for 14 hours. During that time 31 gm. (64% of theory) of2-benzamido-4,5,7,8 tetrahydro-6H-thiozo1o[5,4-d1azepine hydrobromidecrystallized out, which were collected and converted into the free basewith sodium hydroxide. The free base was dissolved in 200 ml. ofmethanol, 6 gm. of ethyleneoxide were added to the solution, and themixture was stirred at room temperature. Thereafter, the methanol wasevaporated, the residue2-benzamido-6 (p hydroxyethyl)-4,5,7,8-tetrahydro6H thiazolo[5,4d]azepine was dissolved in ethanol, and the resultingsolution was acidified was isopropanolic hydrochloric acid, yielding 42%of theory of 2-benzamido-6-(fl hydroxy ethyl)- 4,5,7,8-tetrahydro 6Hthiazolo[5,4-d] azepine hydrochloride, M.P. 146 C. This compound wasthen hydrolized by boiling for 8 hours with aqueous 20% hydr0- chloricacid, the reaction solution was subsequently made alkaline with sodiumhydroxide and then extracted with chloroform, the chloroform extractswere evaporated, the residue-Z-amino 6 (fi-hydroxy ethyl)4,5,7,8-tetrahydro 6H thiazolo[5,4d]azepinewas dissolved in ethanol, thesolution was acidified with isopropanolic hydrochloric acid, and acetonewas added to the acidic solution to precipitate the reaction product.55% of theory of the dihydrochloride, M.P. 192 C. (decomp.), of theformula were obtained.

Analysis.-Calculated for C H N OS-2HCl (mol wt. 286.22) (percent): C,37.81; H, 5.99; N, 14.68. Found (percent): C, 37.65; H, 5. 83; N, 14.67.

EXAMPLE 61 Using a procedure analogous to that described in Example 60,2 amino 6 (fi-hydroxy-propyl)-4,5,7,8- tetrahydro 6Hthiazolo[5,4-d]azepine dihydrochloride, M.P. 221 C. (decomp.), of theformula was prepared from 2-benzamido-4,5,7,8-tetrahydro 6H-thiazolo[5,4-d]az.epine and propyleneoxide. The yield was 43% of theory.

Analysis. Calculated for C I-I N OS-2HC1 (mol. wt. 300.25) (percent): C,39.95; H, 6.38; N, 13.98. Found (percent): C, 40.00; H, 6.47; N, 13.75.

The compounds according to the present invention, that is, thoseembraced by Formulas I and Ia above and their non-toxic acid additionsalts, have useful pharmacodynamic properties. More particularly, thecompounds exhibit hypotensive, sedative, antitussive and antiphlogisticactivities, coupled with very low toxicity, in warm-blooded animals,such as cats, mice and rats. All of the compounds of the instantinvention exhibit all of these pharmacological properties, although oneof these activities may be more pronounced than the others, dependingupon the particular R and R -substitution.

Thus, the hypotensive activity is particularly pronounced in thosecompounds of the Formula I wherein R is alkyl, allyl or an unsubstitutedor substituted aralkyl radical and R is hydrogen. Especially noteworthyis the fact that, among this sub-generic class of compounds, thosewherein R is unsubstituted or substituted aralkyl produce no initialincrease in the blood pressure and only minor sedative elfects.

The effects upon the blood pressure were ascertained on cats undera-D-(+)-glucochloralose/urethane anesthesia. These tests showed that thehypotensive activity is especially pronounced in the followingcompounds:

2-amino-6-benzyl-4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

2-amino-6(p-chloro-benzyl)-4,5,7,8-tetrahydro-6H- thiazolo 5,4-d]azepine,

2-amino-6- (m-bromo-benzyl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d1azepine,

2-amino-6 (4'-methyl-b enzyl) -4,5 ,7, 8-tetrahydro-6H-thiazolo[5,4-d]azepine,

2-amino-6- (p-trifluoromethyl-benzyl) -4,5,7,8-tetrahydro-SH-thiazolo[5,4-d] azepine,

2amino-6- (m-trifluoromethyl-benzyl) -4,5,7,8-tetrahydro-6H-thiazolo5,4-d] azepine, and

2-amino-6- (p-fiuoro-benzyl) -4,5 ,7,8-tetrahydro-6H- thiazolo [5,4-d]azepine.

2-amino-6-butyl-4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine,

Z-amino-6-a1lyl-4,5,7,8-tetrahydro-6H-thiazolo [5 ,4-d] azepine,

2-amino-6-ethyl-4,5 ,7, 8-tetrahydro-6H-oxazolo [5,4-d] azepine, and

2-amino-6-a1ly1-4,5,7,8-tetrahydro-6H-oxazolo [5,4d] azepine.

The sedative activity was ascertained in mice by the standard testmethod of Friebel et al., Arzneimittelforschung, 9, 126- (1959), andthis activity was found to be particularly pronounced in the followingcompounds:

2-amino-6-a1lyl-4,5,7,8-tetrahydro-6H-oxazolo [5 ,4-d] azepine,

2-amino-6-ethyl-4,5 7, 8-tetrahydro- 6-H-thiazolo [5 ,4-d] azepine,

2-amino-6-isopropyl-4,5 ,7, 8-tetrahydro-6H-thiazolo [5 ,4-d] azepine,

2-ethylamino-6-ethyl-4,5 ,7 ,8-tetr ahydro-6H-thiazolo [5,4-d] azepine,and

2ethylamino-6-propyl-4,5 ,7 ,S-tetrahydro -6H-thiazolo [5,4-d] azepine.

The antiphlogistic activity was ascertained, in terms of theanti-exudative efiect against the carrageeninedem'a in the hind paw ofthe rat, by the standard test method of Winter et al., Proc. Soc. Exper.Biol. Med., 111, 544-547 (1962), and against the kaolin-edema in thehind paw of the rat by the method of Hillebrecht, Arzneimittelforschung,4, 607-6 14 (1954). These tests showed that the antiphlogistic activityis particularly pronounced in the following compounds:

2-amino6-allyl-4,5,7,8-tetrahydro-6H-thiazolo [5,4-d1azepine,

2-amylamino-6-allyl-4,5,7,8-tetrahydro6H-thiazolo [5 ,4-d] azepine, and

2-allylamino-o-allyl-4,5,7,8-tetrahydro-6H-thiazolo [5,4-d] azepine.

For pharmaceutical purposes the compounds according to the presentinvention are administered to warm-blooded animals perorally orparenterally as active ingredients in customary dosage unitcompositions, that is, compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one effective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders, solutions, suspensions, emulsions, syrups,suppositories and the like. One effective dosage unit of the compoundsaccording to the present invention is from 0.0033 to 0.167 mgm./kg. bodyweight, preferably 0.0033 to 0.084 mgm./kg. body weight. The averagedaily dose is from 0.0033 to 0.34 mgm./ kg. body weight, preferably from0.0033 to 0.167 mgm./kg. body weight. 7

The following examples illustrate a few dosage unit compositionscomprising a compound of the present invention as an active ingredientand represent the best modes contemplated of putting the invention topractical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 62 Coated pills The pill core composition is compounded from thefollowing ingredients:

Parts 2 amino 6 (p-chlorobenzyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine-2HC1 5.0 Lactose 33.5 Corn starch 10.0 Gelatin1.0 Magnesium stearate 0.5

Total 50.0

Preparation The thiazoloazepine compound is intimately admixed with thelactose and the corn starch, the mixture is moistened with an aqueous10% solution of the gelatin, the moist mass is granulated by forcing itthrough a 1 mm.- mesh screen, the granulate is dried at 40 C. and againpassed through the screen, admixed with the magnesium 'stearate, and thecomposition is compressed into 50 mgm.-

pill cores. The entire procedure must be carried out in a darkened room.The pill cores are then coated with a thin shell consisting essentiallyof a mixture of sugar and talcum, and the coated pills are polished withbeeswax. Each pill contains 5.0 mgm. of the thiazoloazepine compound andis an oral dosage unit composition with elfective hypotensive action.

EXAMPLE 63 Drop solution The solution is compounded from the followingingredients:

Distilled water, q.s. ad 100.0 parts by vol.

Preparation The p-hydroxy-benzoic acid alkyl esters, the oil of aniseand the menthol are dissolved in the ethanol (solution A).

The buffers, the thiazoloazepine compound and the sodium cyclamate aredissolved in distilled water, and the glycerin is added thereto(solution B).

Solution A is stirred into solution B, the mixture is diluted withdistilled water to the indicated volume, the finished solution isfiltered, and the filtrate is filled into brown ml. bottles. 1

All of the above operations must be carried out under exclusion of lightand in an inert gas atmosphere.

1 ml. (about 20 drops) of the solution contains 5 mgm. of thethiazoloazepine compound and is an oral dosage unit composition witheffective hypotensive action.

19 ,EXAMPLE 64 Suppositories The suppository composition is compoundedfrom the following ingredients:

Parts 2-amino-6-(p-chloro-benzyl)-4,5,7,8 tetrahydro-6H-thiazolo[5,4-d]azepine-ZI-ICI 10.0 Suppository base (e.g. cocoabutter) 1690.0

Total 1700.0

Preparation EXAMPLE 65 Hypodermic solution The solution is compoundedfrom the following ingredients:

Parts 2-amino-6-(p-chloro-benzyl)-4,5,7,8-tetrahydro 6H-thiazolo[5,4-d]azepine-2HC1 5.0 Citric acid 7.0 Secondary sodiumphosphate-2H O 3.0 Sodium pyrosulfite 1.0

Distilled water, q.s. ad 1000.0 parts by vol.

Preparation The buffers, the thiazoloazepine compound and the sodiumpyrosulfite are successively dissolved in a sufficient amount ofdistilled water which had previously been boiled and allowed to cool inan atmosphere of carbon dioxide. The solution is diluted to theindicated volume with additional boiled distilled water, filtered untilfree from suspended matter, and the filtrate is filled into brown 1 cc.ampules in an inert gas atmosphere, which are sealed and sterilized for20 minutes at 120 C. The preparation of the solution and the fillingprocedure must be carried out in a darkened room. Each ampule containsmgm. of the thiazoloazepine compound and the contents thereof are aparenterally injectable dosage unit composition with effectivehypotensive action.

A dosage unit composition comprising a compound of the instant inventionmay also contain one or more other active ingredients having the same ordifferent pharmacological properties, as illustrated by the followingexamples.

EXAMPLE 66 Coated pills The pill core composition is compounded from thefollowing ingredients:

Preparation The thiazoloazepine compound, the pyrimidopyrimidinecompound, the digoxin, the potato starch and the lactose are intimatelyadmixed with each other, the mixture is moistened with an ethanolie 10%solution of the polyvinylpyrrolidone, the moist mass is granulated byforcing it through a 1.5 mm.-mesh screen, the granulate is dried at 40C. and again passed through a 1 mm.-mesh screen, the dry 'granulate isadmixed with the magnesium stearate, and the finished composition iscompressed into 120 mgm.-pill cores, which are coated with a thin shellconsisting essentially of a mixture of sugar and talcum, and polishedwith beeswax. Each pill contains 0.2 mgm. of the thiazoloazepinecompound, 25 mgm. of the pyrimidopyrimidine compound and 0.25 mgm. ofdigoxin, and is an oral dosage unit composition with effectivehypotensive, coronary vasodilating and cardiotonic actions.

EXAMPLE 67 Gelatin capsules The capsule filler composition is compoundedfrom the following ingredients:

Preparation The ingredients are intimately and homogeneously admixedwith each other, and mgm. portions of the mixture are filled into opaquegelatin capsules of suitable size. Each capsule contains 5 mgm. of thethiazoloazepine compound and 10 mgm. of codeine phosphate, and itscontents are an oral dosage unit composition with effective hypotensiveand antitussive actions.

Analogously any one of the other compounds embraced by Formulas I andIa, or a non-toxic acid addition salt thereof, may be substituted forthe particular thiazoloazepine salt in Examples 62 through 67. Likewise,the amount of active ingredient in these illustrative examples may bevaried to achieve the dosage unit range set forth above, and the amountsand nature of the inert pharmaceutical carrier ingredients may be variedto meet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. A compound of the formula R is hydrogen, alkyl of 1 to 4 carbonatoms, hydroxyalkyl of 1 to 4 carbon atoms, allyl, cyclohexyl,hexahydrobenzyl, phenyl, phenethyl, benzyl, monoor 21 di-halobenzyl,mono-, dior trimethoxybenzyl, trifl-uoromethyl-benzyl or (alkyl of 1 to3 carbon atomsl benzyl, and R is hydrogen, alkyl of 1 to 5 carbon atoms,allyl,

cyclohexyl, phenyl, benzyl or phenethyl,

or a non-toxic, phanmacologically acceptable acid addition salt thereof.

2. A compound of the formula wherein X is oxygen or sulfur, and R isallyl, alkyl of 1 to 3 carbon atoms, benzyl, halobenzyl,trifluoromethyl-benzyl or methyl-benzyl,

5. A compound according to claim 2, which is 2-amino- 6 (p methylbenzyl) 4,5,7,8 tetrahydro 6H thiazolo[5,4-d]azepine or a nontoxic,pharmacologically acceptable acid addition salt thereof.

6. A compound according to claim 2, which is 2-amino- 6 (ptrifiuoromethyl benzyl) 4,5,7,8 tetrahydro 6H-thiazolo[5,4-d]azepine ora non-toxic, phramacologically acceptable acid addition salt thereof.

7. A compound according to claim 2, which is 2-amino- 6 (mtrifiuoromethyl benzyl) 4,5,7,8 tetrahydro- 6H-thiazolo[5,4-d]azepine ora non-toxic, pharmacologically acceptable acid addition salt thereof.

8. A compound according to claim 2, which is Z-amino- 6 allyl 4,5,7,8tetrahydro 6H thiazolo[5,4-d]azepine or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

9. A compound according to claim 2, which is 2-amino- 6 ethyl 4,5,7,8tetrahydro 6H oxazolo[5,4 d]azepine or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

10. A compound according to claim 2, which is 2- amino 6 allyl 4,5,7,8tetrahydro 6H oxazolo[5,4- d]azepine or a non-toxic, pharmacologicallyacceptable acid addition salt thereof.

No references cited.

RICHARD J. GALLAGHER, Primary Examiner US. Cl. X.R.

